I. Field of the Invention
The present invention relates generally to the field of medicine, including obstetrics. More particularly, it concerns the use of thiazolidinediones, including troglitazone, by itself and in combination with tocolytic agents to prevent or reduce oxytocin-mediated actions such as uterine contractions in premature labor and lactation.
II. Description of Related Art
Preterm birth causes at least 75% of neonatal deaths that cannot be attributed to congenital malformations. A newborn weighing less than 1500 grams is about 200 times more likely to die before becoming a year-old than an infant born with a birthweight of greater than 2500 grams. Preterm birth contributes significantly to developmental delay, visual and hearing impairment, chronic lung disease, and cerebral palsy. Low-birth-weight survivors also have a 10 times greater chance of being neurologically impaired. Even in healthy-appearing preterm infants, academic and family problems occur more frequently than they do with term infants (McCormick, 1985).
Even though preterm birth has continued to present significant problems in the field of obstetrics for many years, the rate of preterm births has remained at the same level since the middle of this century. Numerous and varied therapies are available but much controversy revolves around their efficacies in prevention of prematurity and the management of premature labor (Main, 1995). By controlling uterine contractions and allowing on time delivery, billions of dollars in care for premature infants will be saved.
Preterm labor, defined as spontaneous labor occurring prior to 37 weeks of gestation (with 39 weeks being term), accounts for approximately 1 in 10 births and is the cause of preterm delivery. Preterm delivery is associated with contractions of the uterine muscle, which are likely induced by oxytocin in the blood. Oxytocin action on the uterus is completely dependent upon the increased expression of oxytocin receptors (OTR) in the myometrium just prior to birth. The ability to inhibit the premature rise of OTR or inactivate OTR may be critical in preventing premature onset of labor and birth. The purpose of the invention is to prevent unwanted contractions by preventing an increase in OTR expression and/or preventing oxytocin from binding to OTR. Thus, the use of thiazolidinediones, such as troglitazone, or related compounds that prevent oxytocin from binding to OTR and/or inhibit an increase in OTR should prevent premature labor and labor prior to Caesarian delivery.
Known functions of oxytocin (OT) include smooth muscle contraction during birth (Fuchs et al., 1982; Soloff, 1989), milk ejection during lactation (Soloff, et al., 1979), and prostaglandin release (Hinko and Soloff, 1992). These actions occur as very specifically timed events because the upregulation of OTRs determines the responsiveness of cells to oxytocin. At term, myometrial OTRs rise 2-fold just before labor and fall dramatically immediately after birth. In contrast, OTRs in mammary myoepithelial cells, which contract in response to oxytocin that is reflexively released into the blood as a result of suckling, increase shortly after birth and remain elevated as long as suckling continues. From these two examples, it is clear that the rise in OTR levels dictate tissue specific OT action, and the regulation of OTRs in these two tissues is different. To date, known agents that cause an increase in OTR protein levels include estradiol in the uterus (Fuchs, et al., 1983; Larcher et al., 1995), and glucocorticoids and/or cyclic AMP in rabbit amnion (Hinko and Soloff, 1993), and glucocorticoids and an unknown protein(s) in a human breast tumor cell line, Hs578T (Copland et al., 1999).
OTRs are expressed on cell surface membranes, and the binding of OT from the circulation or arising from paracrine sources sets off a cascade of intracellular events that culminate in cell contraction and/or prostaglandin synthesis. These events are mediated by G proteins tethered to the intracellular portion of OTRs (Strakova and Soloff, 1997). Gi and Gq isotypes have been shown to be coupled to OTRs, and each works through distinct and separate intracellular pathways. Activation of these G proteins results in a rapid rise in intracellular calcium, phosphorylation of mitogen-activated protein (MAP) kinase (ERK 2 and p38) (Hoare et al., 1999). Other events resulting from OT treatment include transcriptional activation of cfos mRNA, a protein vital for cell cycle regulation (Strakova et al., 1998). No specific competitive antagonist exists for oxytocin because oxytocin and vasopressin share a high degree of homology with one another as well as the V1a vasopressin receptor and OTR (Postina et al., 1996 and references therein). Vasopressin at a 10-100 fold concentration will activate the oxytocin receptor. As well, a high affinity antagonist blocking oxytocin binding to the OTR exists but it binds equally well to the vasopressin receptor. Recently, Zingg described 5β-dihydroprogesterone, a progesterone metabolite, to noncompetively bind to the oxytocin receptor and antagonize oxytocin action (Grazzini et al., 1998). However, high concentrations of 100 μM 5β-dihydroprogesterone were needed to inhibit oxytocin induced uterine contractions (Thornton et al. 1999). A noncompetitive inhibitor (e.g. 5β-dihydroprogesterone) binds to a different site for instance on the OTR as opposed to the site that oxytocin binds to activate the OTR. A noncompetitive inhibitor alters the conformation of the molecule that it binds, thereby altering the ability of the activating ligand to bind to the same molecule. These events are only partially reversible once the noncompetitive antagonist binds. Thus, no effective specific competitive antagonist exists clinically for oxytocin and the oxytocin receptor.
By controlling uterine contractions and allowing on time delivery, billions of dollars in costs for premature infant care will be saved. For oxytocin to have biological activity, oxytocin receptors (OTR) must increase. This occurs shortly before birth as well as during breast-feeding to allow secretion of the mother's milk. Mothers who wish not to breast feed their infants could take troglitazone to inhibit oxytocin action.
Troglitazone is currently used clinically in Type 2 diabetic patients to increase insulin sensitivity and thus, increase glucose uptake into cells (thiazolidinediones do not cause hypoglycemia). This drug is taken orally with excellent absorption into the blood stream and few side effects. Troglitazone is marketed for Sankyo by Parke-Davis in the United States. No significant side effects of this drug have been demonstrated with the exception that a small percentage of patients developed idiopathic liver intolerance.